1. Cancer Genetics Flashcards
4 classes of Normal regulatory genes
Growth promoting protooncogenes - ability to control growth (normal) mutated = oncogene
growth inhibiting tumor supressor genes - suppress uncontrolled growth remove or inactivate tumor suppressor gene
genes that regulate apoptosis - not active
genes that regulate DNA repair
Carcinogenesis
Nonlethal genetic/epigenetic changes are the basis of carcinogenesis
initiation of cancer formation
driver mutation- causes the malignant phenotype, single mut that starts process of carcinogen
initiating mutation - first driver mutation, genes with mutation
passenger mutation - no phenotypic consequences, do not contribute to cancer phenotype, more passenger then driver mutations
Accumulation of driver and passenger mutations = cancer
Takes decades which is why cancer risk increases with age
three strikes to cancer
breakthrough phase - a single cell develops a specific driver - gene mutation and begins to divide abnormally
expansion phase - cell develops additional driver mutation that gives rise to benign tumor, basement membrane is in tact
invasion phase - cell develops additional driver - gene mutation in at least one of the indicated pathways enabling it to invade surrounding tissue - metastasize - basement membrane not intact
two-hit hypothesis
in tumor suppressor genes
mutations in both alleles are neccessary to be tumorigeneic and the cancer is recessive
first hit germline - inheritance of a single germ-line mutation increases a chance of a second somatic hit - cancer
second hit somatic line - happens in sporadic forms of cancer by two sequential somatic forms
two-hit hypothesis in RB1 gene
RB1 is a tumor supressor gene in retinoblastoma a rare eye condition
in sporadic RB1 - both alleles of RB1 have to be mutated - two hits for mutation of RB1 are necessary
in inherited RB1 - first hit mutation is inherited however second somatic hit is required for tumorigenesis
Loss of Heterozygosity (LOH)
common genetic event in carcinogenesis of many cancers
a change from a heterozygote state to homozygote state in tumor DNA
strongly associated with the allele of a gene that is inactivated in a first hit and remaining functional allele is deleted in the second hit
examples of tumor suppressor genes such as RB1 and BRCA genes
LOH and ulcerative colitis
in p53 gene LOH occurs in UC-associated dysplasia and malignancy
chronic inflammation of colon can contribute to carcinogenesis by increasing oxidative stress which promotes DNA damage and tumor initiation
Inflammation (colitis) - p53 LOH - indefinite dysplasia (abnormal cells) - low grade dyplasia - high grade dysplasia - carcinoma
viruses can cause cancer by
Oncovirus
viral oncogene expression
genome integrations - viral gene incorporated into host DNA
chronic activation of inflammatory response
classes of oncogene viruses
DNA oncoviruses (EBV, HBV) RNA oncogenes (HTLV-1)
DNA oncovirus lifecycle
DNA -> RNA -> protein
2 life styles
all part of viral genome is expressed, causing viral replication - cell lysis and death
viral DNA is usually integrated into the chromosome randomly, which causes transformation of cells
DNA Oncovirus (EBV)
oral cavity is primary site of infection
EBV infects epithelial cells and naive B cells
EBV genome gets transported into B cells nucleus where replication begins
EBV activates B-cell growth causing Blasting B cells - activated and proliferate
can go into latency (EBV shuts down genes) if resting B gets activated - viral reactivation and shedding - goes through lytic cycle
- priming of naive T cell promotes EBV specific response
DNA oncovirus ( Hep B - HBV)
different from other DNA oncogenes
DNA is transcribed into RNA for both production of viral prteins and genome replication
genomic RNA is transcribes back to DNA
why therapy for HCC fails -
bc of an intracellular viral replication intermediate which is cccDNA (covalently closed circular)
main rol of cccNDA - a template for all viral RNAs -> producing new virons
RNA oncovirus: human T cell luekemia (HTLV-1)
RNA oncovirus are members of retrovirus family
Retrovirus
RNA is copied by reverse transcriptionase to DNA
new DNA copies to RNA
RNA - mRNA - viral protein - virus formation
HTLV-1 causes adult T-cell luekemia/lymphoma (ATLL)
HTLV-1 produces a regulatory protein names Tax which is essential for viral replication and oncogeneic potential fof HTLV-1
Tax functions
tax dysregulates gene expression
in case of DNA damage, Tax disrupts the cell cycle checkpoint and DNA repair causing mutation and cellular transformation
